Hyperthermia Syndrome

Hyperthermia is a rise in core temperature above the hypothalamic set point because heat production or heat gain overwhelms heat loss. It differs from fever, in which the set point rises, so antipyretics do not work. This article concerns the drug-induced, toxin-induced and anesthesia-triggered hyperthermia syndromes. A temperature over 40 degrees Celsius is an emergency, and each hour over 41.5 degrees Celsius sharply raises mortality.

Causes

• Malignant hyperthermia: a pharmacogenetic disorder of skeletal muscle calcium release (RYR1 mutations in about 70% and CACNA1S in a few), triggered by volatile anesthetics (sevoflurane, isoflurane, desflurane) and succinylcholine. Incidence is about 1 in 5000 to 1 in 50,000 anesthetics.
• Sympathomimetic toxicity: cocaine, amphetamines, MDMA and cathinones.
• Serotonin syndrome and neuroleptic malignant syndrome.
• Anticholinergic toxicity, which blocks sweating.
• Salicylate poisoning, which uncouples oxidative phosphorylation, and other uncouplers (dinitrophenol).
• Thyroid storm and baclofen withdrawal.
• Central causes: hypothalamic or brainstem hemorrhage.

In each, muscle hypermetabolism or failed heat dissipation drives the temperature up. Without treatment malignant hyperthermia was fatal in 70 to 80% of cases, and with prompt dantrolene mortality is under 5%. Complications: rhabdomyolysis, hyperkalemia, disseminated intravascular coagulation, acute kidney injury, hepatic failure, cerebral edema and arrhythmia.

• Malignant hyperthermia: a rising end-tidal carbon dioxide (the earliest sign), unexplained tachycardia, masseter or generalized rigidity, mottled skin, and temperature rising by 1 degree Celsius every 5 to 10 minutes
• Sympathomimetic: agitation, sweating, dilated pupils, hypertension
• Anticholinergic: hot dry flushed skin, dilated pupils, urinary retention and absent bowel sounds
• Serotonin syndrome: clonus and hyperreflexia. Neuroleptic malignant syndrome: lead-pipe rigidity and bradykinesia
• Thyroid storm: goiter, tremor and atrial fibrillation
• Dark urine, bleeding and seizures in severe disease
• Red flags: temperature over 40 degrees Celsius, rigidity, hyperkalemia, a creatine kinase over 5000 units/L and falling consciousness

1. Core temperature by rectal, esophageal or bladder probe, repeated every 5 to 15 minutes.
2. Blood tests: arterial blood gas (mixed respiratory and metabolic acidosis), lactate, potassium, calcium, creatinine, creatine kinase (peaking at 12 to 24 hours and sometimes over 100,000 units/L), myoglobin, liver tests, coagulation studies, fibrinogen, glucose.
3. Toxicology: salicylate and paracetamol levels, urine drug screen, and a medication history including recent anesthetics.
4. Thyroid stimulating hormone and free thyroxine when storm is possible, and an ECG.
5. Infection screen (cultures, lumbar puncture when meningism or altered consciousness) because sepsis causes fever and may coexist.
6. Malignant hyperthermia confirmation after recovery: genetic testing for RYR1 and CACNA1S, or an in vitro contracture test on a muscle biopsy.

Differentials: heat stroke, sepsis, meningitis, status epilepticus and delirium tremens.

1. Remove the trigger: stop volatile anesthetics and succinylcholine, change to propofol-based intravenous anesthesia, hyperventilate with 100% oxygen at 10 L/min or more using a clean circuit, and stop the surgery when possible.
2. Dantrolene for malignant hyperthermia: 2.5 mg/kg IV rapid bolus, repeated every 5 minutes until tachycardia, rigidity and temperature settle, up to 10 mg/kg (rarely more). Then 1 mg/kg IV every 4 to 6 hours for 24 to 48 hours. Adverse effects: weakness, phlebitis, hepatotoxicity with prolonged use. Avoid concurrent verapamil or diltiazem (hyperkalemia and collapse).
3. Cooling: cold water spray with a fan, ice packs to the neck, axillae and groin, and cold 0.9% saline 15 mL/kg IV over 15 minutes. Stop active cooling at 38.5 degrees Celsius to avoid overshoot. Paracetamol and aspirin are ineffective.
4. Agitation and sympathomimetic toxicity: diazepam 5 to 10 mg IV every 5 to 10 minutes (children 0.1 to 0.2 mg/kg), titrated to calm.
5. Serotonin syndrome: cyproheptadine 12 mg orally or by nasogastric tube, then 2 mg every 2 hours until improved, then 8 mg every 6 hours (maximum 32 mg a day).
6. Neuroleptic malignant syndrome: stop the dopamine antagonist, dantrolene 1 to 2.5 mg/kg IV, and bromocriptine 2.5 mg by nasogastric tube every 8 hours.
7. Anticholinergic toxicity: physostigmine 0.5 to 2 mg IV over 5 minutes, only when the QRS is normal and there is no tricyclic ingestion.
8. Thyroid storm: propranolol 1 to 2 mg IV over 10 minutes (or 60 to 80 mg orally every 4 hours), propylthiouracil 200 mg orally every 4 hours, hydrocortisone 100 mg IV every 8 hours, and potassium iodide 5 drops every 6 hours starting 1 hour after the thionamide.
9. Salicylate poisoning: sodium bicarbonate 1 to 2 mmol/kg IV, and haemodialysis for severe toxicity.
10. Hyperthermia over 41 degrees Celsius with rigidity: intubate and paralyze with rocuronium 1 mg/kg IV. Avoid succinylcholine.
11. Hyperkalemia: calcium chloride 1 g IV, and insulin 10 units IV with 50 mL of 50% dextrose.
12. Rhabdomyolysis: IV 0.9% saline 200 to 300 mL/h to keep urine output over 1 mL/kg/h. Replace clotting factors for disseminated intravascular coagulation.

Monitor in intensive care for at least 24 hours, since malignant hyperthermia recurs in 20 to 25% within 36 hours. Check creatine kinase every 6 to 12 hours. Refer the patient and relatives for susceptibility testing, and give a medical alert for future anesthetics.